rs203462

Positions:

• chr17-19909228-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007202.4(AKAP10):​c.1936A>G​(p.Ile646Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,612,096 control chromosomes in the GnomAD database, including 125,833 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (14762 hom., cov: 33)
  • Exomes 𝑓: 0.39 (111071 hom.)
• Consequence: AKAP10 NM_007202.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided U:1 B:1
• Conservation: PhyloP100: 3.39

Genes affected

AKAP10 (HGNC:368): (A-kinase anchoring protein 10) This gene encodes a member of the A-kinase anchor protein family. A-kinase anchor proteins bind to the regulatory subunits of protein kinase A (PKA) and confine the holoenzyme to discrete locations within the cell. The encoded protein is localized to mitochondria and interacts with both the type I and type II regulatory subunits of PKA. Polymorphisms in this gene may be associated with increased risk of arrhythmias and sudden cardiac death. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.4074975E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP10	NM_007202.4	c.1936A>G	p.Ile646Val	missense_variant	14/15	ENST00000225737.11	NP_009133.2
AKAP10	NM_001330152.2	c.1762A>G	p.Ile588Val	missense_variant	13/14		NP_001317081.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP10	ENST00000225737.11	c.1936A>G	p.Ile646Val	missense_variant	14/15	1	NM_007202.4	ENSP00000225737.6
AKAP10	ENST00000395536.7	c.1762A>G	p.Ile588Val	missense_variant	13/14	5		ENSP00000378907.3

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64970 AN: 151984 Hom.: 14728 Cov.: 33

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.416

GnomAD3 exomes AF: 0.371 AC: 93016 AN: 250460 Hom.: 18352 AF XY: 0.364 AC XY: 49250 AN XY: 135416

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.182

Gnomad SAS exome AF: 0.297

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.385 AC: 562722 AN: 1459994 Hom.: 111071 Cov.: 37 AF XY: 0.382 AC XY: 277236 AN XY: 726326

Gnomad4 AFR exome AF: 0.595

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.368

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.303

Gnomad4 FIN exome AF: 0.346

Gnomad4 NFE exome AF: 0.393

Gnomad4 OTH exome AF: 0.389

GnomAD4 genome AF: 0.428 AC: 65059 AN: 152102 Hom.: 14762 Cov.: 33 AF XY: 0.424 AC XY: 31542 AN XY: 74368

Gnomad4 AFR AF: 0.584

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.370

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.287

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.415

Alfa AF: 0.385 Hom.: 30014

Bravo AF: 0.444

TwinsUK AF: 0.402 AC: 1490

ALSPAC AF: 0.406 AC: 1564

ESP6500AA AF: 0.581 AC: 2560

ESP6500EA AF: 0.383 AC: 3298

ExAC AF: 0.373 AC: 45349

Asia WGS AF: 0.242 AC: 847 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.374

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Reclassified - variant of unknown significance Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

May 15, 2007

- -

AKAP10-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.49
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.000054	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.0	N;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.31	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.12
MPC		0.18
ClinPred		0.0060	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs203462; hg19: chr17-19812541; COSMIC: COSV56731343; COSMIC: COSV56731343;